Genotype-Guided prescription of Azathioprine reduces the incidence of adverse drug reactions in TPMT intermediate metabolizers to a similar incidence as normal metabolizers
EntityUAM. Departamento de Farmacología
10.1007/s12325-022-02067-8Advances in Therapy 39 (2022): 1743–1753
ISSN0741-238X (print); 1865-8652 (online)
Funded byOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This research received no external funding. G. Villapalos-Garcı´a is co-financed by Instituto de Salud Carlos III (ISCIII) and the European Social Fund (PFIS predoctoral grant, number FI20/00090). M. Navares-Go´mez is financed by the ICI20/00131 Grant, Accio´n Estrate´gica en Salud 2017-2020, ISCIII. Paula Soria-Chacartegui is financed the FPI-UAM2021 predoctoral fellowship. P. Zubiaur’s contract with CIBERehd is financed by the ‘‘Infraestructura de Medicina de Precisio´n asociada a la Ciencia y Tecnologı´a (IMPaCT, IMP/ 00009)’’, Instituto de Salud Carlos III (ISCIII)
SubjectsAdverse drug reactions; Azathioprine; Genotyping; Thiopurines; Precision medicine; TPMT; Medicina
Rights© The Author(s) 2022
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
Introduction: Thiopurine drugs are purine nucleoside analogues used for treatment of different immune-related conditions. To date, different studies highlighted the importance of thiopurine methyltransferase (TPMT) genotyping in patients who initiate treatment with thiopurines to make an adequate dose adjustment. We aimed to investigate the influence of TPMT phenotype, concomitant treatments, and demographic characteristics on the incidence of adverse reactions (ADRs) in patients who start treatment with azathioprine (AZA). Methods: This was an observational and retrospective study. The study population comprised 109 patients who started treatment with AZA following routine TPMT genotyping before June 2019 and who were routinely followed up at Hospital Universitario de La Princesa. The incidence of ADRs and treatment duration were evaluated according to TPMT phenotype. Results: Forty-five men and 64 women were recruited, with a mean age of 67.6 ± 18.5. The medical specialty with the most requests was dermatology (45.9%) and the most frequent disease for which genotyping was requested was bullous pemphigoid (27.5%). All patients were normal metabolizers (NM), except for eight intermediate metabolizers (IM) (7.3%); no poor metabolizers (PM) were found. The initial azathioprine dose was subtherapeutic in both groups (103.2 ± 45.4 mg in NMs and 75 ± 32.3 mg in IMs), increasing during the first months of treatment, especially in NMs (120.3 ± 41.3 vs. 78.6 ± 30.4 mg in IMs, p = 0.011). Most patients (73.4%) received corticosteroids to keep the disease under control; and for 41.2% of NMs, physicians were able to reduce the dose at 6 months post treatment. No IMs completed 6 months of treatment. Hepatotoxicity, gastric intolerance, and blood disorders were the most common ADRs. The incidence of ADRs in the sample was 28.4% (n = 31) with a similar trend between IMs (37.5%) and NMs (27.8%). Patients undergoing concomitant treatment with allopurinol were associated with a higher incidence of ADRs (n = 4, 100% vs. n = 105, 20%; p = 0.002). Conclusion: TPMT genotyping before AZA prescription reduces ADR incidence in IMs to a similar level as NMs in the Spanish population. However, it is important to note no IMs completed 6 months of treatment, suggesting that there may be some differences in drug tolerability according to phenotype. In addition, most NMs are treated with subtherapeutic doses, are poorly followed up, and thus suffer avoidable ADRs. Finally, concomitant therapies that inhibit the xanthine oxidase enzyme (XDH), such as allopurinol, predispose to ADRs. Therefore, pharmacogenetic testing should be integrated as an additional clinical tool, in such a way that each patient receives personalized, precision treatment, where all factors influencing drug response are considered
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Google Scholar:Casajús, Ana - Zubiaur, Pablo - Méndez, Marta - Campodónico, Diana - Gómez, Antía - Navares-Gómez, Marcos - Villapalos-García, Gonzalo - Soria-Chacartegui, Paula - Novalbos, Jesús - Román, Manuel - Mejía Abril, Gina - Ochoa Mazarro, María Dolores - Abad Santos, Francisco
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Villapalos García, Gonzalo; Zubiaur Precioso, Pablo; Ochoa Mazarro, María Dolores; Soria Chacartegui, Paula; Navares Gómez, Marcos; Matas, Miriam; Mejía Abril, Gina; Casajús Rey, Ana; Campodónico, Diana; Román, Manuel; Martín Vílchez, Samuel; Candau Ramos, Carmen; Aldama Martín, Marina; Abad Santos, Francisco